ESRRA

Chr 11

estrogen related receptor alpha

Also known as: ERR1, ERRa, ERRalpha, ESRL1, NR3B1

NCBI Gene: 2101ENSG00000173153UniProt: P11474

The protein encoded by this gene is a nuclear receptor that is most closely related to the estrogen receptor. This protein acts as a site-specific transcription factor and interacts with members of the PGC-1 family of transcription cofactors to regulate the expression of most genes involved in cellular energy production as well as in the process of mitochondrial biogenesis. A processed pseudogene of ESRRA is located on chromosome 13q12.1. [provided by RefSeq, Jun 2019]

63
ClinVar variants
8
Pathogenic / LP
0.60
pLI score
0
Active trials
Clinical Summary— ESRRA
⚡
Population Constraint (gnomAD)
Moderately constrained gene (pLI 0.60) — some intolerance to loss-of-function variants.
📋
ClinVar Variants
8 Pathogenic / Likely Pathogenic· 51 VUS of 63 total submissions

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.49LOEUF
pLI 0.597
Z-score 2.99
OE 0.19 (0.09–0.49)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
2.08Z-score
OE missense 0.63 (0.56–0.72)
161 obs / 254.1 exp
Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.19 (0.09–0.49)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.0.63 (0.56–0.72)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.0.96
0≤1.21.6
LoF obs/exp: 3 / 15.8Missense obs/exp: 161 / 254.1Syn Z: 0.33

ClinVar Variant Classifications

63 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic6
Likely Pathogenic2
VUS51
Likely Benign2
Benign2
6
Pathogenic
2
Likely Pathogenic
51
VUS
2
Likely Benign
2
Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
0
0
6
0
6
Likely Pathogenic
0
0
2
0
2
VUS
0
49
2
0
51
Likely Benign
0
0
0
2
2
Benign
0
1
0
1
2
Total05010363

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

ESRRA · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
ESRRA (estrogen related receptor alpha) is a critical regulator of intestinal homeostasis through activation of autophagic flux via gut microbiota.
Kim S et al.·Autophagy
2021
Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing.
Sun Y et al.·J Transl Med
2024
Oestrogen Receptor Alpha in Myocyte Maintains Muscle Regeneration in Duchenne Muscular Dystrophy.
Huang X et al.·J Cachexia Sarcopenia Muscle
2025
Comprehensive Analysis of ESRRA in Endometrial Cancer.
Wang S et al.·Technol Cancer Res Treat
2021
Replication of associations between LRP5 and ESRRA variants and bone density in premenopausal women.
Giroux S et al.·Osteoporos Int
2008
Exome Sequencing Implicates DGKZ , ESRRA , and GXYLT1 for Modulating Granuloma Formation in Crohn Disease.
Harris RA et al.·J Pediatr Gastroenterol Nutr
2023
Estrogen-related receptor gene expression associates with sex differences in cortical atrophy in isolated REM sleep behavior disorder.
Filiatrault M et al.·Nat Commun
2025
VSEAMS: a pipeline for variant set enrichment analysis using summary GWAS data identifies IKZF3, BATF and ESRRA as key transcription factors in type 1 diabetes.
Burren OS et al.·Bioinformatics
2014
Transcriptomic meta-analysis reveals ERRα-mediated oxidative phosphorylation is downregulated in Fuchs' endothelial corneal dystrophy.
Zhang X et al.·PLoS One
2023Meta-analysis
Estrogen related receptor alpha: Potential modulator of age-related macular degeneration.
Somers FM et al.·Curr Opin Pharmacol
2024Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
ESRRA-ATG5-Mediated mitophagy enhances arginine metabolism to alleviate diabetic kidney disease.
Hu H et al.·Autophagy
2025
Convergent Genetic Architecture in Concurrent Anorectal Malformations and Hypospadias: The ESRRA-STARD8 Axis as a Key Regulator of Urogenital Development.
Goswami C et al.·J Indian Assoc Pediatr Surg
2025🔓 Open Access
Nuclear receptor ESRRA promotes ERα-positive breast cancer through dual action on super enhancers and promoters to regulate gene transcriptional programs.
Zheng ZZ et al.·Sci Bull (Beijing)
2025
Study on the anticancer mechanism of hydroxygenkwanin in esophageal cancer via the ESRRA signaling pathway.
Wang Y et al.·Cancer Genet
2025Functional
ESRRA (estrogen related receptor, alpha) induces ribosomal protein RPLP1-mediated adaptive hepatic translation during prolonged starvation.
Tripathi M et al.·Autophagy
2025🔓 Open Access
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov

No active trials found for this gene.

Search ClinicalTrials.gov →

External Resources

Links to major genomics databases and tools